Process for the production of an abuse-proofed dosage form

ABSTRACT

The present invention relates to a process for the production of abuse-proofed, thermoformed dosage forms containing, apart from one or more active ingredients with potential for abuse and optionally physiologically acceptable auxiliary substances, at least one synthetic or natural polymer with a breaking strength of at least 500 N.

This application is a continuation of U.S. patent application Ser. No.13/962,098, filed Aug. 8, 2013, now pending, which is a continuation ofU.S. patent application Ser. No. 12/140,718, now abandoned, which is adivision of U.S. patent application Ser. No. 11/471,438, filed Jun. 20,2006, now abandoned, which is, in turn, a continuation of InternationalPatent Application No. PCT/EP04/14679, filed on Dec. 23, 2004, whichclaims priority of German Patent Application No. 103 61 596.2, filedDec. 24, 2003.

The present invention relates to a process for the production of solidpharmaceutical dosage forms with at least reduced potential for abuse,by

-   -   a) shaping a formulation mixture containing at least one active        ingredient with potential for abuse and at least one synthetic        or natural polymer (C), which exhibits a breaking strength of at        least 500 N, into formed articles by application of force,    -   b) optionally singulating the formed articles and optionally in        each case grading them by size and,    -   c) after or during heating at least to the softening point of        the polymer (C), exposing the formed articles to force until        they have a breaking hardness of at least 500 N, optionally        providing them with a cover and optionally mixing all the formed        articles back together again.

BACKGROUND OF INVENTION

Many pharmaceutical active ingredients, in addition to having excellentactivity in their appropriate application, also have potential forabuse, i.e. they can be used by an abuser to bring about effects otherthan those intended.

Opiates, for example, which are highly active in combating severe tovery severe pain, are frequently used by abusers to induce a state ofnarcosis or euphoria.

In order to make abuse possible, the corresponding dosage forms, such astablets or capsules are comminuted, for example ground in a mortar, bythe abuser, the active ingredient is extracted from the resultant powderusing a preferably aqueous liquid and the resultant solution, optionallyafter being filtered through cotton wool or cellulose wadding, isadministered parenterally, in particular intravenously. An additionalphenomenon of this kind of administration, in comparison with abusiveoral administration, is a further accelerated increase in activeingredient levels giving the abuser the desired effect, namely the“kick” or “rush”. This kick is also obtained if the powdered dosage formis administered nasally, i.e. is sniffed.

Since delayed-release dosage forms containing active ingredients withpotential for abuse do not give rise to the kick desired by the abuserwhen taken orally even in abusively high quantities, such dosage formsare also comminuted and extracted in order to be abused.

U.S. Pat. No. 4,070,494 proposed adding a swellable agent to the dosageform in order to prevent abuse. When water is added to extract theactive ingredient, this agent swells and ensures that the filtrateseparated from the gel contains only a small quantity of activeingredient.

The multilayer tablet disclosed in WO 95/20947 is based on a similarapproach to preventing parenteral abuse, said tablet containing theactive ingredient with potential for abuse and at least one gel former,each in different layers.

WO 03/015531 A2 discloses another approach to preventing parenteralabuse. A dosage form containing an analgesic opioid and a dye as anaversive agent is described therein. The colour released by tamperingwith the dosage form is intended to discourage the abuser from using thedosage form which has been tampered with.

Another known option for complicating abuse involves adding antagoniststo the active ingredients to the dosage form, for example naloxone ornaltrexone in the case of opiates, or compounds which cause aphysiological defence response, such as for example ipecacuanha (ipecac)root.

Since, however, as in the past, it is in most cases necessary for thepurposes of abuse to pulverise dosage forms containing an activeingredient suitable for abuse, it was the object of the presentinvention to provide a process for the production of abuse-proofeddosage forms with which the pulverisation of the dosage form whichprecedes abuse using the means conventionally available to the potentialabuser is complicated or prevented and thus to produce a dosage form foractive ingredients with potential for abuse, which, when correctlyadministered, ensures the desired therapeutic action, but from which theactive ingredient cannot be converted into a form suitable for abusesimply by pulverisation.

SUMMARY OF THE INVENTION

Said object has been achieved by the process according to the inventionfor the production of solid pharmaceutical dosage forms with at leastreduced potential for abuse which is characterised in that

-   -   a) a formulation mixture containing at least one active        ingredient with potential for abuse, at least one synthetic or        natural polymer (C), which exhibits a breaking strength of at        least 500 N, and optionally auxiliary substances (B) is shaped        into formed articles by application of force,    -   b) the formed articles are optionally singulated and optionally        in each case graded by size and,    -   c) after or during heating at least to the softening point of        the polymer (C), the formed articles are exposed to force until        they have a breaking hardness of at least 500 N, they are        optionally provided with a cover and all the formed articles are        optionally mixed back together again.

DETAILED DESCRIPTION

The use of polymers (C) having the stated minimum breaking strength inthe process according to the invention, preferably in quantities suchthat the dosage form also exhibits such a minimum breaking strength,means that pulverisation of the dosage form is considerably moredifficult using conventional means, so considerably complicating orpreventing the subsequent abuse.

If comminution is inadequate, parenteral, in particular intravenous,administration cannot be performed safely or extraction of the activeingredient therefrom takes too long for the abuser or there is no “kick”when taken orally, as release is not instantaneous.

According to the invention, comminution is taken to mean pulverisationof the dosage form by the application of force with conventional meanswhich are conventionally available to an abuser, such as for example apestle and mortar, a hammer, a mallet or other usual means forpulverisation, wherein the proportion of fines which may arise (particlesize equal to or smaller than 0.3 mm) must not exceed 5 wt. %.

The dosage form obtained according to the invention is thus suitable forpreventing parenteral, nasal and/or oral abuse of pharmaceutical activeingredients with potential for abuse.

Pharmaceutical active ingredients with potential for abuse are known tothe person skilled in the art, as are the quantities thereof to be usedand processes for the production thereof, and may be present in thedosage form according to the invention as such, in the form of thecorresponding derivatives thereof, in particular esters or ethers, or ineach case in the form of corresponding physiologically acceptablecompounds, in particular in the form of the salts or solvates thereof,as racemates or stereoisomers. The dosage form obtained according to theinvention is also suitable for the administration of a plurality ofactive ingredients. It is preferably used for the administration of onespecific active ingredient.

The dosage form obtained according to the invention is in particularsuitable for preventing the abuse of at least one pharmaceutical activeingredient which is selected from the group comprising opiates, opioids,tranquillisers, preferably benzodiazepines, barbiturates, stimulants andfurther narcotics.

The dosage form obtained according to the invention is very particularlypreferably suitable for preventing abuse of an opiate, opioid,tranquilliser or another narcotic, which is selected from the groupcomprisingN-{{1-[2-(4-ethyl-5-oxo-2-tetrazolin-1-yl)ethyl]-4-methoxymethyl-4-piperidyl}propionanilide(alfentanil), 5,5-diallylbarbituric acid (allobarbital), allylprodine,alphaprodine,8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine(alprazolam), 2-diethylaminopropiophenone (amfepramone),(±)-α-methylphenethylamine (amphetamine),2-(α-methylphenethylamino)-2-phenylacetonitrile (amphetaminil),5-ethyl-5-isopentylbarbituric acid (amobarbital), anileridine,apocodeine, 5,5-diethylbarbituric acid (barbital), benzylmorphine,bezitramide, 7-bromo-5-(2-pyridyl)-1H-1,4-benzodiazepine-2(3H)-one(bromazepam),2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine(brotizolam), 17-cyclopropylmethyl-4,5α-epoxy-7α[(S)-1-hydroxy-1,2,2-trimethyl-propy1]-6-methoxy-6,14-endo-ethanomorphinan-3-ol(buprenorphine), 5-butyl-5-ethylbarbituric acid (butobarbital),butorphanol,(7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl)dimethylcarbamate (camazepam), (1S,2S)-2-amino-1-phenyl-1-propanol(cathine/D-norpseudoephedrine),7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-ylamine 4-oxide(chlordiazepoxide),7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione(clobazam), 5-(2-chlorophenyl)-7-nitro-1H-1,4-benzodiazepin-2(3H)-one(clonazepam), clonitazene,7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylicacid (clorazepate),5-(2-chlorophenyl)-7-ethyl-1-methyl-1H-thieno[2,3-e][1,4]diazepin-2(3H)-one(clotiazepam),10-chloro-11b(2-chlorophenyl)-2,3,7,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(5H)-one(cloxazolam), (−)-methyl-[3β-benzoyloxy-2[3(1αH,5αH)-tropanecarboxylate] (cocaine), 4,5α-epoxy-3-methoxy-17-methyl-7-morphinen-6α-ol(codeine), 5-(1-cyclohexenyl)-5-ethylbarbituric acid (cyclobarbital),cyclorphan, cyprenorphine,7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2(3H)-one(delorazepam), desomorphine, dextromoramide,(+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl)propionate(dextropropoxyphene), dezocine, diampromide, diamorphone,7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (diazepam),4,5α-epoxy-3-methoxy-17-methyl-6α-morphinanol (dihydrocodeine),4,5α-epoxy-17-methyl-3,6a-morphinandiol (dihydromorphine), dimenoxadol,dimephetamol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol(dronabinol), eptazocine,8-chloro-6-phenyl-4H[1,2,4]-triazolo[4,3-(a)][1,4]benzodiazepine(estazolam), ethoheptazine, ethylmethylthiambutene, ethyl[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylate](ethyl loflazepate), 4,5α-epoxy-3-ethoxy-17-methyl-7-morphinen-6α-ol(ethylmorphine), etonitazene,4,5α-epoxy-7α-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endo-etheno-morphinan-3-ol(etorphine), N-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine(fencamfamine), 7-[2-(α-methylphenethylamino)ethyl]-theophylline)(fenethylline), 3-(α-methylphenethylamino)propionitrile (fenproporex),N-(1-phenethyl-4-piperidyl)propionanilide (fentanyl),7-chloro-5-(2-fluorophenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one(fludiazepam),5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepin-2(3H)-one(flunitrazepam),7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2(3H)-one(flurazepam),7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepin-2(3H)-one(halazepam),10-bromo-11b-(2-fluorophenyl)-2,3,7,11b-tetrahydro[1,3]oxazolo[3,2-d][1,4]benzodiazepin-6(5H)-one(haloxazolam), heroin, 4,5α-epoxy-3-methoxy-17-methyl-6-morphinanone(hydrocodone), 4,5α-epoxy-3-hydroxy-17-methyl-6-morphinanone(hydromorphone), hydroxypethidine, isomethadone, hydroxymethylmorphinan,11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]oxazino[3,2-d][1,4]benzodiazepine-4,7(6H)-dione(ketazolam), 1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone(ketobemidone), (3S,6S)-6-dimethylamino-4,4-diphenylheptan-3-yl acetate(levacetylmethadol (LAAM)), (−)-6-dimethylamino-4,4-diphenol-3-heptanone(levomethadone), (−)-17-methyl-3-morphinanol (levorphanol),levophenacylmorphane, lofentanil,6-(2-chlorophenyl)-2-(4-methyl-1-piperazinylmethylene)-8-nitro-2H-imidazo[1,2-a][1,4]-benzodiazepin-1(4H)-one (loprazolam),7-chloro-5-(2-chlorophenyl)-3-hydroxy-1H-1,4-benzodiazepin-2(3H)-one(lorazepam),7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1H-1,4-benzodiazepin-2(3H)-one(lormetazepam),5-(4-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol(mazindol), 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine(medazepam), N-(3-chloropropyl)-α-methylphenethylamine (mefenorex),meperidine, 2-methyl-2-propyltrimethylene dicarbamate (meprobamate),meptazinol, metazocine, methylmorphine, N,α-dimethylphenethylamine(methamphetamine), (±)-6-dimethylamino-4,4-diphenol-3 heptanone(methadone), 2-methyl-3-o-tolyl-4(3H)-quinazolinone (methaqualone),methyl [2-phenyl-2-(2-piperidyl)acetate] (methylphenidate),5-ethyl-1-methyl-5-phenylbarbituric acid (methylphenobarbital),3,3-diethyl-5-methyl-2,4-piperidinedione (methyprylon), metopon,8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5a][1,4]benzodiazepine(midazolam), 2-(benzhydrylsulfinyl)acetamide (modafinil),4,5α-epoxy-17-methyl-7-morphinen-3,6α-diol (morphine), myrophine,(±)-trans-3-(1,1-dimethylheptyl)-7,8,10,10α-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo-[b,d]pyran-9(6αH)-one(nabilone), nalbuphene, nalorphine, narceine, nicomorphine,1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nimetazepam),7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nitrazepam),7-chloro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nordazepam),norlevorphanol, 6-dimethylamino-4,4-diphenyl-3-hexanone (normethadone),normorphine, norpipanone, the exudation from plants belonging to thespecies Papaver somniferum (opium),7-chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (oxazepam),(cis-trans)-10-chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d[1,4]benzodiazepin-6-(5H-)-one(oxazolam), 4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone(oxycodone), oxymorphone, plants and parts of plants belonging to thespecies Papaver somniferum (including the subspecies setigerum) (Papaversomniferum), papaveretum, 2-imino-5-phenyl-4-oxazolidinone (pernoline),1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol(pentazocine), 5-ethyl-5-(1-methylbutyl)-barbituric acid(pentobarbital), ethyl-(1-methyl-4-phenyl-4-piperidinecarboxylate)(pethidine), phenadoxone, phenomorphane, phenazocine, phenoperidine,piminodine, pholcodeine, 3-methyl-2-phenylmorpholine (phenmetrazine),5-ethyl-5-phenylbarbituric acid (phenobarbital),α,α-dimethylphenethylamine (phentermine),7-chloro-5-phenyl-1-(2-propynyl)-1H-1,4-benzodiazepin-2(3H)-one(pinazepam), α-(2-piperidyl)benzhydryl alcohol (pipradrol),1′-(3-cyano-3,3-diphenylpropyl)[1,4′-bipiperidine]-4′-carboxamide(piritramide),7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one(prazepam), profadol, proheptazine, promedol, properidine, propoxyphene,N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, methyl{3-[4-methoxycarbonyl-4-(N-phenylpropanamido)piperidino]propanoate}(remifentanil), 5-sec-butyl-5-ethylbarbituric acid (secbutabarbital),5-allyl-5-(1-methylbutyl)-barbituric acid (secobarbital),N-{4-methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl}propionanilide(sufentanil),7-chloro-2-hydroxy-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one(temazepam),7-chloro-5-(1-cyclohexenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one(tetrazepam), ethyl(2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate) (tilidine (cisand trans)), tramadol,8-chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(triazolam), 5-(1-methylbutyl)-5-vinylbarbituric acid (vinylbital),(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,(1R,2R,4S)-2-(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol,(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)phenol,(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,(2R,3R)-1-dimethylamino-3(3-methoxyphenyl)-2-methyl-pentan-3-ol,(1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol,preferably as racemate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(4-isobutoxyphenyl)-propionate,3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)phenyl2-(6-methoxy-naphthalen-2-yl)-propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(4-isobutyl-phenyl)-propionate,3-(2-dimethylaminomethyl-cyclohex-1-enyl)-phenyl2-(6-methoxy-naphthalen-2-yl)-propionate,(RR-SS)-2-acetoxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenylester,(RR-SS)-2-hydroxy-4-trifluoromethyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-4-chloro-2-hydroxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-4-methyl-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-4-methoxy-benzoic acid3-(2-dimethylaminomethyl-1-hydroxycyclohexyl)-phenyl ester,(RR-SS)-2-hydroxy-5-nitro-benzoic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester,(RR-SS)-2′,4′-difluoro-3-hydroxy-biphenyl-4-carboxylic acid3-(2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-phenyl ester togetherwith corresponding stereoisomeric compounds, in each case thecorresponding derivatives thereof, in particular amides, esters orethers, and in each case the physiologically acceptable compoundsthereof, in particular the salts and solvates thereof, particularlypreferably hydrochlorides.

The dosage form according to the invention is particularly suitable forpreventing abuse of an opioid active ingredient selected from among thegroup comprising oxycodone, hydromorphone, morphine, tramadol and thephysiologically acceptable derivatives or compounds thereof, preferablythe salts and solvates thereof, preferably the hydrochlorides thereof.

The dosage form according to the invention is furthermore in particularsuitable for preventing abuse of an opioid active ingredient selectedfrom among the group comprising(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,(2R,3R)-1-dimethylamino-3-(3-methoxyphenyl)-2-methyl-pentan-3-ol,(1RS,3RS,-6RS)-6-dimethylaminomethyl-1-(3-methoxyphenyl)-cyclohexane-1,3-diol, (1R,2R)-3-(2dimethylaminonethyl-cyclohexyl)phenol, the physiologically acceptablesalts thereof, preferably hydrochlorides, physiologically acceptableenantiomers, stereoisomers, diastereomers and racemates and thephysiologically acceptable derivatives thereof, preferably ethers,esters or amides.

These compounds and the process for the production thereof are describedin EP-A-693475 and EP-A-780369 respectively. The correspondingdescriptions are hereby introduced as a reference and are deemed to bepart of the disclosure.

In order to achieve the necessary breaking strength, at least onesynthetic or natural polymer (C) which exhibits a breaking strength,measured using the method disclosed in the present application, of atleast 500 N is used in the process according to the invention.

Preferably, at least one polymer is selected for this purpose from amongthe group comprising polyalkylene oxides, preferably polymethyleneoxides, polyethylene oxides, polypropylene oxides, polyethylenes,polypropylenes, polyvinyl chlorides, polycarbonates, polystyrenes,polyacrylates, the copolymers thereof, and mixtures of at least two ofthe stated polymer classes or polymers. The polymers are distinguishedby a molecular weight of at least 0.5 million, determined by rheologicalmeasurements. Thermoplastic polyalkylene oxides, such as polyethyleneoxides, with a molecular weight of at least 0.5 million, preferably ofat least 1 million to 15 million, determined by rheologicalmeasurements, are very particularly preferred. These polymers have aviscosity at 25° C. of 4500 to 17600 cP, measured on a 5 wt. % aqueoussolution using a model RVF Brookfield viscosimeter (spindle no.2/rotational speed 2 rpm), of 400 to 4000 cP, measured on a 2 wt. %aqueous solution using the stated viscosimeter (spindle no. 1 or3/rotational speed 10 rpm) or of 1650 to 10000 cP, measured on a 1 wt. %aqueous solution using the stated viscosimeter (spindle no. 2/rotationalspeed 2 rpm).

The polymers are preferably used in powder form. They may be soluble inwater.

Polymers (C) are present in the formulation mixture or in the dosageforms produced according to the invention in an amount of at least 30wt. %, preferably of at least 50 wt. % to 99.9 wt. %, relative to thetotal quantity.

In order to achieve the necessary breaking strength of the dosage formobtained according to the invention, it is furthermore possibleadditionally to use at least one natural or synthetic wax (D) with abreaking strength, measured using the method disclosed in the presentapplication, of at least 500 N.

Waxes with a softening point of at least 60° C. are preferably used.Carnauba wax and beeswax are particularly preferred. Carnauba wax isvery particularly preferred.

Carnauba wax is a natural wax which is obtained from the leaves of thecarnauba palm and has a softening point of at least 80° C. When the waxcomponent (D) is additionally used, it is used together with at leastone polymer (C) in quantities such that the dosage form exhibits abreaking strength of at least 500 N.

Auxiliary substances (B) which may be used are those known auxiliarysubstances which are conventional for the formulation of solid dosageforms. These are preferably plasticisers, such as polyethylene glycols,auxiliary substances which influence active ingredient release,preferably hydrophobic or hydrophilic, preferably hydrophilic polymers,very particularly preferably hydroxypropylmethylcellulose, and/orantioxidants. Suitable antioxidants are ascorbic acid,butylhydroxyanisole, butylhydroxytoluene, salts of ascorbic acid,monothioglycerol, phosphorous acid, vitamin C, vitamin E and thederivatives thereof, sodium bisulfite, particularly preferablybutylhydroxytoluene (BHT) or butylhydroxyanisole (BHA) and α-tocopherol.

The antioxidant is preferably used in quantities of 0.01 to 10 wt. %,preferably of 0.03 to 5 wt. %, relative to the total weight of thedosage form.

The abuse-proofed, solid dosage form is produced by initially mixing theactive ingredient, the component (C), optionally the wax component (D),optionally auxiliary substances (B) and optionally at least one of theoptionally present further abuse-preventing components (a)-(f) listedbelow and the resultant formulation mixture is shaped by application offorce into formed articles, preferably the dosage form.

The formulation mixture is prepared in a mixer known to the personskilled in the art. The mixer may, for example, be a roll mixer, shakingmixer, shear mixer or compulsory mixer.

The resultant formulation mixture is preferably directly shaped byapplication of force into formed articles, preferably the dosage form,preferably without exposure to heat. The formulation mixture may, forexample, be formed into tablets by direct tabletting. In directtabletting, pressing is performed with the assistance of a tablettingtool, i.e. bottom punch, top punch and die.

The formulation mixture may also first be granulated and then shaped.

Shaping is preferably performed with application of force, a force ofgreater than or equal to 0.5 kN, preferably of 1 to 100 kN, beingapplied. The force is preferably exerted with the assistance of a press,preferably a tablet press, with shaping rollers or shaping beltsequipped with rollers. The formulation mixture may also be extruded withthe assistance of an extruder to yield a strand which is singulated intoformed articles having the desired size. If heating also proceeds duringapplication of force, heating should remain below 60° C.

If the formulation mixture is processed to yield multiparticulate formedarticles, such as granules, pellets, these should have a minimum size of0.5 mm, preferably a size of 1 to 3.5 mm. Before further processing,these formed articles, if they are not of a largely uniform size, arepreferably graded by size. This grading may proceed with the assistanceof a screening method.

In the further process step c), the formed articles are again exposed toforce, wherein either before or during application of force the formedarticles are heated at least to the softening point of the polymer (C),preferably to greater than or equal to 60° C. A force of at least 0.1kN, preferably of 1 kN up to 120 kN, particularly preferably up to 100kN, very particularly preferably up to at most 90 kN, is applied. As isknown to any person skilled in the art, the duration of the treatmentwith force is dependent on the strength of the applied force, on theheating before or during the application of force and optionally on thesize of the formed articles and may be determined by simple tests suchthat, after the application of force, the formed articles exhibit abreaking hardness of at least 500 N, measured using the method statedbelow.

The necessary heating may preferably be monitored by a temperaturemeasurement in the interior of a formed article with the assistance of atemperature sensor.

Force may be applied continuously or discontinuously with the assistanceof the above-stated apparatus. The entire process according to theinvention may proceed continuously and discontinuously.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an apparatus with which the formed articles 1, in thepresent case tablets, are exposed after heating to force between shapingbelts with pressure rollers 2. The shaping belts, which run parallel oneabove and one below, are here provided with means for accommodating thetablets. A foil/film, preferably an aluminium foil or a functionalfoil/film (not shown in FIG. 1), may also run with the shaping beltssuch that, during the application of force, the formed article 1, in thepresent case a tablet, may simultaneously be provided with a cover.Formed articles covered in this manner may be divided into a desirednumber of joined dosage forms, such as for example blister packs.

The formed articles may be heated in the most varied manner. Heating inovens, i.e. with the assistance of a heated gas atmosphere, or withradiant heat is preferred. Heating may also be effected byelectromagnetic waves, in particular by microwaves. Apart from ovenswhich are loaded in discontinuous batches, tunnel ovens, in which theformed articles are continuously conveyed through these ovens, are alsosuitable. In a further preferred process variant, heat is alsointroduced into the formed articles (1) via the conveyor belt.

Heating preferably proceeds under a protective gas atmosphere,particularly preferably under a nitrogen atmosphere.

As already explained, force may be applied with the assistance of atablet press, the formed articles being supplied heated to the die. Inparticular, this may also be combined with jacketed tablet production,wherein the outer envelope material which is applied by pressure mayconsist of auxiliary substances or of an active ingredient/auxiliarysubstance mixture.

A procedure in which the application of force according to c) iseffected by shaping rollers (see FIG. 1) is particularly preferred. Inthis procedure, the heated formed articles (1) are supplied to twocontrarotating pressure rollers (2) which comprise profile recesses toaccommodate the individual tablets. The application of force onto theheated formed articles (1) between the rollers gives rise to the desiredbreaking strength of the dosage form.

This procedure is also suitable for continuous performance, wherein theformed articles are supplied to the rollers by a conveyor belt, by meansof which, before the force is applied to the formed articles, saidarticles are previously directly exposed to heating in the tunnel oven,under a radiation source or through the belt.

FIG. 2 shows a further preferred embodiment in which, the formedarticles (1) are conveyed in a carrier (3), which comprises a profilefor the formed articles (1) and is particularly preferably configured asa continuous conveyor belt. This carrier (3) is brought into alignmentwith a second shaping belt (5), which likewise comprises a partialprofile of the formed articles (1), and forced is exerted onto bothsides of the carrier belts.

FIG. 3 shows the measurement of the breaking strength of a tablet, inparticular the tablet (4) adjustment device (6) used for this purposebefore and during the measurement. To this end, the tablet (4) is heldbetween the upper pressure plate (1) and the lower pressure plate (3) ofthe force application apparatus (not shown) with the assistance of two2-part clamping devices, which are in each case firmly fastened (notshown) with the upper and lower pressure plate once the spacing (5)necessary for accommodating and centring the tablet to be measured hasbeen established. The spacing (5) may be established by moving the2-part clamping devices horizontally outwards or inwards in each case onthe pressure plate on which they are mounted.

The tablets deemed to be resistant to breaking under a specific loadinclude not only those which have not broken but also those which mayhave suffered plastic deformation under the action of the force.

The breaking strength of the dosage forms obtained according to theinvention is determined by the stated measurement method, with dosageforms other than tablets also being tested.

In the process according to the invention, it may be advantageous toapply release agents onto the shaped profiles, in which force is appliedto the formed articles, and onto the formed articles so that the formedarticles may readily be detached again from the carrier belts or thepressure rollers. Suitable release agents are pharmaceuticallyconventional release agents, such as for example talcum, magnesiumstearate. Preferred release agents are those which do not change theirstate of aggregation at the temperature of the process.

It may furthermore be advantageous to provide mechanical release aids inthe apparatus with which force is applied, which release aids activelyeject the formed articles after the application of force. This may forexample proceed by holes through which a gas is blown under pressure orby mechanical punches.

The method according to the invention may be accelerated and optimisedby rapidly cooling the formed articles after the application of forceaccording to c). This may proceed, for example by conveying the formedarticles into or through a cooling chamber or by introducing them into acooling medium, such as for example into a liquid gas.

The dosage forms obtained according to the invention are distinguishedin that, due to their hardness, they cannot be pulverised, for exampleby grinding even if cooled to low temperatures. This virtually rules outoral or parenteral, in particular intravenous or nasal abuse.

However, in order to prevent any possible abuse in the event ofcomminution and/or pulverisation of the dosage form obtained accordingto the invention which has nevertheless been achieved by application ofextreme force, the dosage forms obtained according to the invention may,in a preferred embodiment, contain further agents which complicate orprevent abuse as auxiliary substances (B).

The abuse-proofed dosage form obtained according to the invention, whichcomprises, apart from one or more active ingredients with potential forabuse, at least one hardening polymer (C) optionally auxiliarysubstances (B) and optionally at least one wax (D), may accordingly alsocomprise at least one of the following components (a)-(e) as optionalfurther auxiliary substances (B):

-   (a) at least one substance which irritates the nasal passages and/or    pharynx,-   (b) at least one viscosity-increasing agent, which, with the    assistance of a necessary minimum quantity of an aqueous liquid,    preferably as an aqueous extract obtained from the dosage form,    forms a gel which preferably remains visually distinguishable when    introduced into a further quantity of an aqueous liquid,-   (c) at least one antagonist for each of the active ingredients with    potential for abuse,-   (d) at least one emetic,-   (e) at least one dye as an aversive agent,-   (f) at least one bitter substance.

Components (a) to (f) are additionally each individually suitable forabuse-proofing the dosage form according to the invention. Accordingly,component (a) is preferably suitable for proofing the dosage formagainst nasal, oral and/or parenteral, preferably intravenous, abuse,component (b) is preferably suitable for proofing against parenteral,particularly preferably intravenous and/or nasal abuse, component (c) ispreferably suitable for proofing against nasal and/or parenteral,particularly preferably intravenous, abuse, component (d) is preferablysuitable for proofing against parenteral, particularly preferablyintravenous, and/or oral and/or nasal abuse, component (e) is suitableas a visual deterrent against oral or parenteral abuse and component (f)is suitable for proofing against oral or nasal abuse. Combined useaccording to the invention of at least one of the above-statedcomponents makes it possible still more effectively to complicate abuseof dosage forms obtained according to the invention.

In one embodiment, the dosage form according to the invention may alsocomprise two or more of components (a)-(f) in a combination, preferably(a), (b) and optionally (c) and/or (f) and/or (e) or (a), (b) andoptionally (d) and/or (f) and/or (e).

In another embodiment, the dosage form obtained according to theinvention may comprise all of components (a)-(f).

If the dosage form obtained according to the invention comprises anabuse-preventing component (a), substances which irritate the nasalpassages and/or pharynx which may be considered according to theinvention are any substances which, when administered accordingly viathe nasal passages and/or pharynx, bring about a physical reaction whichis either so unpleasant for the abuser that he/she does not wish to orcannot continue administration, for example burning, or physiologicallycounteracts taking of the corresponding active ingredient, for exampledue to increased nasal secretion or sneezing. These substances whichconventionally irritate the nasal passages and/or pharynx may also bringabout a very unpleasant sensation or even unbearable pain whenadministered parenterally, in particular intravenously, such that theabuser does not wish to or cannot continue taking the substance.

Particularly suitable substances which irritate the nasal passagesand/or pharynx are those which cause burning, itching, an urge tosneeze, increased formation of secretions or a combination of at leasttwo of these stimuli. Appropriate substances and the quantities thereofwhich are conventionally to be used are known per se to the personskilled in the art or may be identified by simple preliminary testing.

The substance which irritates the nasal passages and/or pharynx ofcomponent (a) is preferably based on one or more constituents or one ormore plant parts of at least one hot substance drug.

Corresponding hot substance drugs are known per se to the person skilledin the art and are described, for example, in “PharmazeutischeBiologie—Drogen and ihre Inhaltsstoffe” by Prof. Dr. Hildebert Wagner,2nd., revised edition, Gustav Fischer Verlag, Stuttgart-New York, 1982,pages 82 et seq. The corresponding description is hereby introduced as areference and is deemed to be part of the disclosure.

A dosage unit is taken to mean a separate or separable administrationunit, such as for example a tablet or a capsule.

One or more constituents of at least one hot substance drug, selectedfrom the group consisting of Allii sativi bulbus (garlic), Asari rhizomacum herba (Asarum root and leaves), Calami rhizoma (calamus root),Capsici fructus (capsicum), Capsici fructus acer (cayenne pepper),Curcumae longae rhizoma (turmeric root), Curcumae xanthorrhizae rhizoma(Javanese turmeric root), Galangae rhizoma (galangal root), Myristicaesemen (nutmeg), Piperis nigri fructus (pepper), Sinapis albaesemen/Erucae semen (white mustard seed), Sinapis nigri semen (blackmustard seed), Zedoariae rhizoma (zedoary root) and Zingiberis rhizoma(ginger root), particularly preferably from the group consisting ofCapsici fructus (capsicum), Capsici fructus acer (cayenne pepper) andPiperis nigri fructus (pepper) may preferably be added as component (a)to the dosage form obtained by the process according to the invention.

The constituents of the hot substance drugs preferably compriseo-methoxy(methyl)phenol compounds, acid amide compounds, mustard oils orsulfide compounds or compounds derived therefrom.

Particularly preferably, at least one constituent of the hot substancedrugs is selected from the group consisting of myristicin, elemicin,isoeugenol, β-asarone, safrole, gingerols, xanthorrhizol, capsaicinoids,preferably capsaicin, capsaicin derivatives, such asN-vanillyl-9E-octadecenamide, dihydrocapsaicin, nordihydrocapsaicin,homocapsaicin, norcapsaicin and nomorcapsaicin, piperine, preferablytranspiperine, glucosinolates, preferably based on non-volatile mustardoils, particularly preferably based on p-hydroxybenzyl mustard oil,methylmercapto mustard oil or methylsulfonyl mustard oil, and compoundsderived from these constituents.

The dosage form obtained according to the invention may preferablycontain the plant parts of the corresponding hot substance drugs in aquantity of 0.01 to 30 wt. %, particularly preferably of 0.1 to 0.5 wt.%, in each case relative to the total weight of the dosage unit.

If one or more constituents of corresponding hot substance drugs areused, the quantity thereof in a dosage unit according to the inventionpreferably amounts to 0.001 to 0.005 wt. %, relative to the total weightof the dosage unit.

Another option for preventing abuse of the dosage form obtainedaccording to the invention consists in adding at least oneviscosity-increasing agent as a further abuse-preventing component (b)to the dosage form, which, with the assistance of a necessary minimumquantity of an aqueous liquid, forms a gel with the extract obtainedfrom the dosage form, which gel is virtually impossible to administersafely and preferably remains visually distinguishable when introducedinto a further quantity of an aqueous liquid.

For the purposes of the present invention, visually distinguishablemeans that the active ingredient-containing gel formed with theassistance of a necessary minimum quantity of aqueous liquid, whenintroduced, preferably with the assistance of a hypodermic needle, intoa further quantity of aqueous liquid at 37° C., remains substantiallyinsoluble and cohesive and cannot straightforwardly be dispersed in sucha manner that it can safely be administered parenterally, in particularintravenously. The material preferably remains visually distinguishablefor at least one minute, preferably for at least 10 minutes.

The increased viscosity of the extract makes it more difficult or evenimpossible for it to be passed through a needle or injected. If the gelremains visually distinguishable, this means that the gel obtained onintroduction into a further quantity of aqueous liquid, for example byinjection into blood, initially remains in the form of a largelycohesive thread, which, while it may indeed be broken up mechanicallyinto smaller fragments, cannot be dispersed or even dissolved in such amanner that it can safely be administered parenterally, in particularintravenously. In combination with at least one optionally presentcomponent (a) to (e), this additionally leads to unpleasant burning,vomiting, bad flavour and/or visual deterrence.

Intravenous administration of such a gel would most probably result inobstruction of blood vessels, associated with serious damage to thehealth of the abuser.

In order to verify whether a viscosity-increasing agent is suitable ascomponent (b) for use in the dosage form obtained according to theinvention, the active ingredient is mixed with the viscosity-increasingagent and suspended in 10 ml of water at a temperature of 25° C. If thisresults in the formation of a gel which fulfils the above-statedconditions, the corresponding viscosity-increasing agent is suitable forpreventing or averting abuse of the dosage forms according to theinvention.

If component (b) is added to the dosage form obtained according to theinvention, one or more viscosity-increasing agents are used which areselected from the group consisting of microcrystalline cellulose with 11wt. % carboxymethylcellulose sodium (Avicel® RC 591),carboxymethylcellulose sodium (Blanose®, CMC-Na C300P®, FrimulsionBLC-5®, Tylose C300 P®)), polyacrylic acid (Carbopol® 980 NF, Carbopol®981), locust bean flour (Cesagum® LA-200, Cesagum® LID/150, Cesagum®LN-1), pectins, preferably from citrus fruits or apples (Cesapectin® HMMedium Rapid Set), waxy maize starch (C*Gel 04201®), sodium alginate(Frimulsion ALG (E401)®), guar flour (Frimulsion BM®, Polygum 26/1-756),iota-carrageenan (Frimulsion D021®), karaya gum, gellan gum (KelcogelF®, Kelcogel LT100®), galactomannan (Meyprogat 150 ®), tara stone flour(Polygum 43/1 ®), propylene glycol alginate (Protanal-Ester SD-LB®),sodium hyaluronate, tragacanth, tara gum (Vidogum SP 200®), fermentedpolysaccharide welan gum (K1A96), xanthan gum (Xantural 180®). Xanthansare particularly preferred. The names stated in brackets are the tradenames by which the materials are known commercially. In general, aquantity of 0.1 to 20 wt. %, particularly preferably of 0.1 to 15 wt. %,relative to the total weight of the dosage form, of the statedviscosity-increasing agent(s) is sufficient to fulfil the above-statedconditions.

The component (b) viscosity-increasing agents, where provided, arepreferably present in the dosage form according to the invention inquantities of greater than or equal to 5 mg per dosage unit, i.e. peradministration unit.

In a particularly preferred embodiment of the present invention, theviscosity-increasing agents used as component (b) are those which, onextraction from the dosage form with the necessary minimum quantity ofaqueous liquid, form a gel which encloses air bubbles. The resultantgels are distinguished by a turbid appearance, which provides thepotential abuser with an additional optical warning and discourageshim/her from administering the gel parenterally.

Component (C) may also optionally serve as an additionalviscosity-increasing agent, which forms a gel with the assistance of anecessary minimum quantity of aqueous liquid.

It is also possible to formulate the viscosity-increasing agent and theother constituents in the dosage form obtained according to theinvention in a mutually spatially separated arrangement.

In order to discourage and prevent abuse, the dosage form obtainedaccording to the invention may furthermore comprise component (c),namely one or more antagonists for the active ingredient or activeingredients with potential for abuse, wherein the antagonists arepreferably spatially separated from the remaining constituents of thedosage form obtained according to the invention and, when correctlyused, do not exert any effect.

Suitable antagonists for preventing abuse of the active ingredients areknown per se to the person skilled in the art and may be present in thedosage form obtained according to the invention as such or in the formof corresponding derivatives, in particular esters or ethers, or in eachcase in the form of corresponding physiologically acceptable compounds,in particular in the form of the salts or solvates thereof.

If the active ingredient present in the dosage form is an opiate or anopioid, the antagonist used is preferably an antagonist selected fromthe group comprising naloxone, naltrexone, nalmefene, nalid, nalmexone,nalorphine or naluphine, in each case optionally in the form of acorresponding physiologically acceptable compound, in particular in theform of a base, a salt or solvate. The corresponding antagonists, wherecomponent (c) is provided, are preferably used in a quantity of greaterthan or equal to 1 mg, particularly preferably in a quantity of 3 to 100mg, very particularly preferably in a quantity of 5 to 50 mg per dosageform, i.e. per administration unit.

If the dosage form obtained according to the invention comprises astimulant as active ingredient, the antagonist is preferably aneuroleptic, preferably at least one compound selected from the groupconsisting of haloperidol, promethazine, fluphenazine, perphenazine,levomepromazine, thioridazine, perazine, chlorpromazine,chlorprothixine, zuclopentixol, flupentixol, prothipendyl, zotepine,benperidol, pipamperone, melperone and bromperidol.

The dosage form obtained according to the invention preferably comprisesthese antagonists in a conventional therapeutic dose known to the personskilled in the art, particularly preferably in a quantity of twice tothree times the conventional dose per administration unit.

If the combination to discourage and prevent abuse of the dosage formobtained according to the invention comprises component (d), it maycomprise at least one emetic, which is preferably present in a spatiallyseparated arrangement from the other components of the dosage formaccording to the invention and, when correctly used, is intended not toexert its effect in the body.

Suitable emetics for preventing abuse of an active ingredient are knownper se to the person skilled in the art and may be present in the dosageform obtained according to the invention as such or in the form ofcorresponding derivatives, in particular esters or ethers, or in eachcase in the form of corresponding physiologically acceptable compounds,in particular in the form of the salts or solvates thereof.

An emetic based on one or more constituents of ipecacuanha (ipecac)root, preferably based on the constituent emetine may preferably beconsidered in the dosage form obtained according to the invention, asare, for example, described in “Pharmazeutische Biologie—Drogen and ihreInhaltsstoffe” by Prof. Dr. Hildebert Wagner, 2nd, revised edition,Gustav Fischer Verlag, Stuttgart, N.Y., 1982. The correspondingliterature description is hereby introduced as a reference and is deemedto be part of the disclosure.

The dosage form obtained according to the invention may preferablycomprise the emetic emetine as component (d), preferably in a quantityof greater than or equal to 3 mg, particularly preferably of greaterthan or equal to 10 mg and very particularly preferably in a quantity ofgreater than or equal to 20 mg per dosage form, i.e. administrationunit.

Apomorphine may likewise preferably be used as an emetic in theabuse-proofing according to the invention, preferably in a quantity of≧3 mg, particularly preferably of ≧5 mg and very particularly preferablyof ≧7 mg per administration unit.

If the dosage form obtained according to the invention containscomponent (e) as an additional abuse-preventing auxiliary substance, theuse of such a dye brings about an intense coloration of a correspondingaqueous solution, in particular when the attempt is made to extract theactive ingredient for parenteral, preferably intravenous administration,which coloration may act as a deterrent to the potential abuser. Oralabuse, which conventionally begins by means of aqueous extraction of theactive ingredient, may also be prevented by this coloration. Suitabledyes and the quantities required for the necessary deterrence may befound in WO 03/015531, wherein the corresponding disclosure should bedeemed to be part of the present disclosure and is hereby introduced asa reference.

If the dosage form obtained according to the invention containscomponent (f) as a further abuse-preventing auxiliary substance, thisaddition of at least one bitter substance and the consequent impairmentof the flavour of the dosage form additionally prevents oral and/ornasal abuse.

Suitable bitter substances and the quantities effective for use may befound in US-2003/0064099 A1, the corresponding disclosure of whichshould be deemed to be the disclosure of the present application and ishereby introduced as a reference. Suitable bitter substances arepreferably aromatic oils, preferably peppermint oil, eucalyptus oil,bitter almond oil, menthol, fruit aroma substances, preferably aromasubstances from lemons, oranges, limes, grapefruit or mixtures thereof,and/or denatonium benzoate. Denatonium benzoate is particularlypreferred.

The solid dosage form obtained according to the invention is suitablefor oral, vaginal or rectal administration, preferably for oraladministration, to humans and animals. The dosage form is preferably notin film form. The orally administrable dosage form according to theinvention may assume multiparticulate form, preferably in the form ofmicrotablets, microcapsules, micropellets, granules, spheroids, beads orpellets, optionally packaged in capsules or pressed into tablets. Themultiparticulate forms are preferably of a minimum size of 0.5 mm,particularly preferably in the range from 1 to 3.5 mm. Depending on thedesired dosage form, conventional auxiliary substances (B) areoptionally also used for the formulation of the dosage form.

In a further preferred embodiment, the dosage form according to theinvention assumes the form of a tablet, a capsule or is in the form ofan oral osmotic therapeutic system (OROS), preferably if at least onefurther abuse-preventing component (a)-(f) is also present.

If components (c) and/or (d) and/or (f) are present in the dosage formobtained according to the invention, care must be taken to ensure thatthey are formulated in such a manner or are present in such a low dosethat, when correctly administered, the dosage form is able to bringabout virtually no effect which impairs the patient or the efficacy ofthe active ingredient.

If the dosage form produced according to the invention containscomponent (d) and/or (f), the dosage must be selected such that, whencorrectly orally administered, no negative effect is caused. If,however, the intended dosage of the dosage form is exceededinadvertently, in particular by children, or in the event of abuse,nausea or an inclination to vomit or a bad flavour are produced. Theparticular quantity of component (d) and/or (f) which can still betolerated by the patient in the event of correct oral administration maybe determined by the person skilled in the art by simple preliminarytesting.

If, however, irrespective of the fact that the dosage form producedaccording to the invention is virtually impossible to pulverise, thedosage form containing the components (c) and/or (d) and/or (f) isprovided with protection, these components should preferably be used ata dosage which is sufficiently high that, when abusively administered,they bring about an intense negative effect on the abuser. This ispreferably achieved by spatial separation of at least the activeingredient or active ingredients from components (c) and/or (d) and/or(f), wherein the active ingredient or active ingredients is/are presentin at least one subunit (X) and components (c) and/or (d) and/or (f)is/are present in at least one subunit (Y), and wherein, when the dosageform is correctly administered, components (c), (d) and (f) do not exerttheir effect on taking and/or in the body and the remaining componentsof the formulation, in particular component (C), are identical.

If the dosage form according to the invention comprises at least 2 ofcomponents (c) and (d) or (f), these may each be present in the same ordifferent subunits (Y). Preferably, when present, all the components (c)and (d) and (f) are present in one and the same subunit (Y).

For the purposes of the present invention, subunits are solidformulations, which in each case, apart from conventional auxiliarysubstances known to the person skilled in the art, contain the activeingredient(s), preferably also at least one polymer (C) and theoptionally present component (D) and optionally at least one of theoptionally present components (a) and/or (b) and/or (e) or preferably ineach case at least one polymer (C) and optionally (D) and theantagonist(s) and/or emetic(s) and/or component (e) and/or component (f)and optionally at least one of the optionally present components (a)and/or (b). Care must here be taken to ensure that each of the subunitsis formulated in accordance with the above-stated process according tothe invention, if the mechanical skill is desired or required.

One substantial advantage of the separated formulation of activeingredients from components (c) or (d) or (f) in subunits (X) and (Y) ofthe dosage form produced according to the invention is that, whencorrectly administered, components (c) and/or (d) and/or (f) are hardlyreleased on taking and/or in the body or are released in such smallquantities that they exert no effect which impairs the patient ortherapeutic success or, on passing through the patient's body, they areonly liberated in locations where they cannot be sufficiently absorbedto be effective. When the dosage form is correctly administered,preferably hardly any of components (c) and/or (d) and/or (f) isreleased into the patient's body or they go unnoticed by the patient.

The person skilled in the art will understand that the above-statedconditions may vary as a function of the particular components (c), (d)and/or (f) used and of the formulation of the subunits or the dosageform. The optimum formulation for the particular dosage form may bedetermined by simple preliminary testing. What is vital, if necessaryfor abuse prevention, is that each subunit contains the polymer (C) andhas been formulated in the stated manner and produced according to theinvention.

Should, contrary to expectations, the abuser succeed in comminuting sucha dosage form according to the invention, which comprises components (c)and/or (e) and/or (d) and/or (f) in subunits (Y), for the purpose ofabusing the active ingredient and obtain a powder which is extractedwith a suitable extracting agent, not only the active ingredient butalso the particular component (c) and/or (e) and/or (f) and/or (d) willbe obtained in a form in which it cannot readily be separated from theactive ingredient, such that when the dosage form which has beentampered with is administered, in particular by oral and/or parenteraladministration, it will exert its effect on taking and/or in the bodycombined with an additional negative effect on the abuser correspondingto component (c) and/or (d) and/or (f) or, when the attempt is made toextract the active ingredient, the coloration will act as a deterrentand so prevent abuse of the dosage form.

A dosage form according to the invention, in which the active ingredientor active ingredients is/are spatially separated from components (c),(d) and/or (e), preferably by formulation in different subunits, may beformulated in many different ways, wherein the corresponding subunitsmay each be present in the dosage form according to the invention in anydesired spatial arrangement relative to one another, provided that theabove-stated conditions for the release of components (c) and/or (d) arefulfilled.

The person skilled in the art will understand that component(s) (a)and/or (b) which are optionally also present may preferably beformulated in the dosage form produced according to the invention bothin the particular subunits (X) and (Y) and in the form of independentsubunits corresponding to subunits (X) and (Y), provided that neitherthe abuse-proofing nor the active ingredient release in the event ofcorrect administration is impaired by the nature of the formulation andthe polymer (C) is preferably included in the formulation andformulation is preferably carried out in accordance with the processaccording to the invention.

In a preferred embodiment of the dosage form produced according to theinvention, subunits (X) and (Y) are present in multiparticulate form,wherein granules, spheroids, beads or pellets are preferred and the sameform, i.e. shape, is selected for both subunit (X) and subunit (Y), suchthat it is not possible to separate subunits (X) from (Y) by mechanicalselection. The multiparticulate forms are preferably of a size in therange from 0.5 to 3.5 mm, preferably of 0.5 to 2 mm.

The subunits (X) and (Y) in multiparticulate form may also preferably bepackaged in a capsule or be press-moulded into a tablet, wherein thefinal formulation in each case proceeds in such a manner that thesubunits (X) and (Y) are also retained in the resultant dosage form.

The multiparticulate subunits (X) and (Y) of identical shape should alsonot be visually distinguishable from one another so that the abusercannot separate them from one another by simple sorting. This may, forexample, be achieved by the application of identical coatings which,apart from this disguising function, may also incorporate furtherfunctions, such as, for example, delayed release of one or more activeingredients or provision of a finish resistant to gastric juices on theparticular subunits.

The multiparticulate subunits may also be formulated as an oral dosageform as a slurry or suspension in pharmaceutically safe suspendingmedia.

In a further preferred embodiment of the present invention, subunits (X)and (Y) are in each case arranged in layers relative to one another.

The layered subunits (X) and (Y) are preferably arranged for thispurpose vertically or horizontally relative to one another in the dosageform produced according to the invention, wherein in each case one ormore layered subunits (X) and one or more layered subunits (Y) may bepresent in the dosage form, such that, apart from the preferred layersequences (X)-(Y) or (X)-(Y)-(X), any desired other layer sequences maybe considered, optionally in combination with layers containingcomponents (a) and/or (b).

Another preferred dosage form produced according to the invention is onein which subunit (Y) forms a core which is completely enclosed bysubunit (X), wherein a separation layer (Z) may be present between saidlayers. Such a structure is preferably also suitable for theabove-stated multiparticulate forms, wherein both subunits (X) and (Y)and an optionally present separation layer (Z), which should preferablysatisfy the hardness requirement according to the invention, are thenformulated in one and the same multiparticulate form using the processaccording to the invention.

In a further preferred embodiment of the dosage form produced accordingto the invention, the subunit (X) forms a core, which is enclosed bysubunit (Y), wherein the latter comprises at least one channel whichleads from the core to the surface of the dosage form.

The dosage form produced according to the invention may comprise,between one layer of the subunit (X) and one layer of the subunit (Y),in each case one or more, preferably one, optionally swellableseparation layer (Z) which serves to separate subunit (X) spatially from(Y).

If the dosage form produced according to the invention comprises thelayered subunits (X) and (Y) and an optionally present separation layer(Z) in an at least partially vertical or horizontal arrangement, thedosage form preferably takes the form of a tablet, a coextrudate or alaminate, which has been produced using the process according to theinvention.

In one particularly preferred embodiment, the entirety of the freesurface of subunit (Y) and optionally at least part of the free surfaceof subunit(s) (X) and optionally at least part of the free surface ofthe optionally present separation layer(s) (Z) may be coated with atleast one barrier layer (Z′) which prevents release of component (c)and/or (e) and/or (d) and/or (f). The barrier layer (Z′) shouldpreferably also fulfil the hardness conditions according to theinvention.

Another particularly preferred embodiment of the dosage form producedaccording to the invention comprises a vertical or horizontalarrangement of the layers of subunits (X) and (Y) and at least one pushlayer (p) arranged therebetween, and optionally a separation layer (Z),in which dosage form the entirety of the free surface of the layerstructure consisting of subunits (X) and (Y), the push layer and theoptionally present separation layer (Z) is provided with a semipermeablecoating (E), which is permeable to a release medium, i.e. conventionallya physiological liquid, but substantially impermeable to the activeingredient and to component (c) and/or (d) and/or (f), and wherein thiscoating (E) comprises at least one opening for release of the activeingredient in the area of subunit (X).

A corresponding dosage form is known to the person skilled in the art,for example under the name oral osmotic therapeutic system (OROS), asare suitable materials and methods for the production thereof, interalia from U.S. Pat. No. 4,612,008, U.S. Pat. No. 4,765,989 and U.S. Pat.No. 4,783,337. The corresponding descriptions are hereby introduced as areference and are deemed to be part of the disclosure.

In a further preferred embodiment, the subunit (X) of the dosage formproduced according to the invention is in the form of a tablet, the edgeface and optionally one of the two main faces of which is covered with abarrier layer (Z′) containing component (c) and/or (d) and/or (f).

The person skilled in the art will understand that the auxiliarysubstances of the subunit(s) (X) or (Y) and of the optionally presentseparation layer(s) (Z) and/or of the barrier layer(s) (Z′) used in theproduction according to the invention of the respective dosage form willvary as a function of the arrangement thereof in the dosage form, themode of administration and as a function of the particular activeingredient of the optionally present components (a) and/or (b) and/or(e) and of component (c) and/or (d) and/or (f). The materials which havethe requisite properties are in each case known per se to the personskilled in the art.

If release of component (c) and/or (d) and/or (f) from subunit (Y) ofthe dosage form produced according to the invention is prevented withthe assistance of a cover, preferably a barrier layer, the subunit mayconsist of conventional materials known to the person skilled in theart, providing that they contain at least one polymer (C) and optionally(D) and have preferably been produced according to the invention.

If a corresponding barrier layer (Z′) is not provided to prevent releaseof component (c) and/or (d) and/or (f), the materials of the subunitsshould be selected such that release of the particular component (c)and/or (d) from subunit (Y) is virtually ruled out.

The materials which are stated below to be suitable for production ofthe barrier layer may preferably be used for this purpose.

Preferred materials are those which are selected from the groupcomprising alkylcelluloses, hydroxyalkylcelluloses, glucans,scleroglucans, mannans, xanthans, copolymers ofpoly[bis(p-carboxyphenoxy)propane and sebacic acid, preferably in amolar ratio of 20:80 (commercially available under the name Polifeprosan20®), carboxymethylcelluloses, cellulose ethers, cellulose esters,nitrocelluloses, polymers based on (meth)acrylic acid and the estersthereof, polyamides, polycarbonates, polyalkylenes, polyalkyleneglycols, polyalkylene oxides, polyalkylene terephthalates, polyvinylalcohols, polyvinyl ethers, polyvinyl esters, halogenated polyvinyls,polyglycolides, polysiloxanes and polyurethanes and the copolymersthereof.

Particularly suitable materials may be selected from the groupcomprising methylcellulose, ethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, celluloseacetate, cellulose propionate (of low, medium or high molecular weight),cellulose acetate propionate, cellulose acetate butyrate, celluloseacetate phthalate, carboxymethylcellulose, cellulose triacetate, sodiumcellulose sulfate, polymethyl methacrylate, polyethyl methacrylate,polybutyl methacrylate, polyisobutyl methacrylate, polyhexylmethacrylate, polyisodecyl methacrylate, polylauryl methacrylate,polyphenyl methacrylate, polymethyl acrylate, polyisopropyl acrylate,polyisobutyl acrylate, polyoctadecyl acrylate, polyethylene, low densitypolyethylene, high density polyethylene, polypropylene, polyethyleneglycol, polyethylene oxide, polyethylene terephthalate, polyvinylalcohol, polyvinyl isobutyl ether, polyvinyl acetate and polyvinylchloride.

Particularly suitable copolymers may be selected from the groupcomprising copolymers of butyl methacrylate and isobutyl methacrylate,copolymers of methyl vinyl ether and maleic acid of high molecularweight, copolymers of methyl vinyl ether and maleic acid monoethylester, copolymers of methyl vinyl ether and maleic anhydride andcopolymers of vinyl alcohol and vinyl acetate.

Further materials which are particularly suitable for formulating thebarrier layer are starch-filled polycaprolactone (WO98/20073), aliphaticpolyesteramides (DE 19 753 534 A1, DE 19 800 698 A1, EP 0 820 698 A1),aliphatic and aromatic polyester urethanes (DE 19822979),polyhydroxyalkanoates, in particular polyhydroxybutyrates,polyhydroxyvalerates, casein (DE 4 309 528), polylactides andcopolylactides (EP 0 980 894 A1). The corresponding descriptions arehereby introduced as a reference and are deemed to be part of thedisclosure.

The above-stated materials may optionally be blended with furtherconventional auxiliary substances known to the person skilled in theart, preferably selected from the group comprising glycerylmonostearate, semi-synthetic triglyceride derivatives, semi-syntheticglycerides, hydrogenated castor oil, glyceryl palmitostearate, glycerylbehenate, polyvinylpyrrolidone, gelatine, magnesium stearate, stearicacid, sodium stearate, talcum, sodium benzoate, boric acid and colloidalsilica, fatty acids, substituted triglycerides, glycerides,polyoxyalkylene glycols and the derivatives thereof.

If the dosage form produced according to the invention comprises aseparation layer (Z′), said layer, like the uncovered subunit (Y), maypreferably consist of the above-stated materials described for thebarrier layer. The person skilled in the art will understand thatrelease of the active ingredient or of component (c) and/or (d) from theparticular subunit may be controlled by the thickness of the separationlayer.

The dosage form produced according to the invention exhibits controlledrelease of the active ingredient. It is preferably suitable for repeateddaily administration to patients, such as for example for combattingpain in human patients.

The dosage form produced according to the invention may comprise one ormore active ingredients at least partially in a further delayed-releaseform, wherein delayed release may be achieved with the assistance ofconventional materials and methods known to the person skilled in theart, for example by embedding the active ingredient in a delayed-releasematrix or by the application of one or more delayed-release coatings.Active ingredient release must, however, be controlled such that theabove-stated conditions are fulfilled in each case, for example that, inthe event of correct administration of the dosage form, the activeingredient or active ingredients are virtually completely releasedbefore the optionally present component (c) and/or (d) can exert animpairing effect.

Addition of materials effecting controlled release must moreover notimpair the necessary hardness.

Controlled release from the dosage form produced according to theinvention is preferably achieved by embedding the active ingredient in amatrix. The auxiliary substances acting as matrix materials controlactive ingredient release. Matrix materials may, for example, behydrophilic, gel-forming materials, from which active ingredient releaseproceeds mainly by diffusion, or hydrophobic materials, from whichactive ingredient release proceeds mainly by diffusion from the pores inthe matrix.

Physiologically acceptable, hydrophobic materials which are known to theperson skilled in the art may be used as matrix materials. Polymers,particularly preferably cellulose ethers, cellulose esters and/oracrylic resins are preferably used as hydrophilic matrix materials.Ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose,hydroxymethylcellulose, poly(meth)acrylic acid and/or the derivativesthereof, such as the salts, amides or esters thereof are veryparticularly preferably used as matrix materials.

Matrix materials prepared from hydrophobic materials, such ashydrophobic polymers, waxes, fats, long-chain fatty acids, fattyalcohols or corresponding esters or ethers or mixtures thereof are alsopreferred. Mono- or diglycerides of C12-C30 fatty acids and/or C12-C30fatty alcohols and/or waxes or mixtures thereof are particularlypreferably used as hydrophobic materials.

It is also possible to use mixtures of the above-stated hydrophilic andhydrophobic materials as matrix materials.

Component (C) and the optionally present component (D), which serve toachieve the breaking strength of at least 500 N which is obtainedaccording to the invention, may furthermore themselves serve asadditional matrix materials.

If the dosage form produced according to the invention is intended fororal administration, it may also preferably comprise a coating which isresistant to gastric juices and dissolves as a function of the pH valueof the release environment.

By means of this coating, it is possible to ensure that the dosage formproduced according to the invention passes through the stomachundissolved and the active ingredient is only released in theintestines. The coating which is resistant to gastric juices preferablydissolves at a pH value of between 5 and 7.5.

Corresponding materials and methods for the controlled release of activeingredients and for the application of coatings which are resistant togastric juices are known to the person skilled in the art, for examplefrom “Coated Pharmaceutical Dosage Forms—Fundamentals, ManufacturingTechniques, Biopharmaceutical Aspects, Test Methods and Raw Materials”by Kurt H. Bauer, K. Lehmann, Hermann P. Osterwald, Rothgang, Gerhart,1st edition, 1998, Medpharm Scientific Publishers. The correspondingliterature description is hereby introduced as a reference and is deemedto be part of the disclosure.

Method for Determining Breaking Strength

-   A) In order to verify whether a polymer may be used as component (C)    or (D), the polymer is pressed to form a tablet with a diameter of    10 mm and a height of 5 mm using a force of 150 N at a temperature    which at least corresponds to the softening point of the polymer and    is determined with the assistance of a DSC diagram of the polymer.    Using tablets produced in this manner, breaking strength is    determined with the apparatus described below in accordance with the    method for determining the breaking strength of tablets published in    the European Pharmacopoeia 1997, page 143, 144, method no. 2.9.8.    The apparatus used for the measurement is a single column bench    model materials tester with the designation “TMTC-FR2.5 TH.D09” from    Zwick GmbH & Co. KG, Ulm, Germany, Fmax=2.5 kN with a maximum draw    of 1150 mm, which should be set up with one column and one spindle,    a clearance behind of 100 mm and a test speed adjustable between 0.1    and 800 mm/min together with testControl software. Measurement is    performed using a pressure piston with screw-in inserts and a    cylinder (diam. 10 mm), a force transducer, Fmax. 1 kN, diameter=8    mm, class 0.5 from 10 N, class 1 from 2 N to ISO 7500-1, with    manufacturer's test certificate M to DIN 55350-18 (Zwick gross force    Fmax=1.45 kN) (all apparatus from Zwick GmbH & Co. KG, Ulm, Germany)    with order no. BTC-FR 2.5 TH. D09 for the tester, order no. BTC-LC    0050N. P01 for the force transducer, order no. BO 70000 S06 for the    centring device.

The invention is explained below with reference to Examples. Theseexplanations are given merely by way of example and do not restrict thegeneral concept of the invention.

EXAMPLES

Tramadol hydrochloride was used as the active ingredient in a series ofExamples. Tramadol hydrochloride was used, despite tramadol not being anactive ingredient which conventionally has potential for abuse, becauseit is not governed by German narcotics legislation, so simplifying theexperimental work Tramadol is moreover a member of the opioid class withexcellent water solubility.

Example 1

Components Per tablet Complete batch Tramadol HCl 100.0 mg  60.0 gPolyethylene oxide, NF, MFI 221.0 mg 132.6 g (190° C. at 21.6 kg/10min)MW 7,000,000 (Polyox WSR 303, Dow Chemicals)Hydroxypropylmethylcellulose  20.0 mg  12.0 g 100,000 cP (Metholose 90SH 100,000) Magnesium stearate  9.0 mg  5.4 g Total weight 350.0 mg210.0 g

Tramadol hydrochloride and polyethylene oxide powder and hydroxypropylmethylcellulose were mixed in a free-fall mixer. The magnesium stearatepowder was then mixed in. The powder mixture was pressed into tablets ona Korsch EK0 eccentric press. The tabletting tool has a diameter of 10mm and a radius of curvature of 8 mm. These tablets were furtherprocessed with the assistance of a laboratory heat sealer (Kopplaboratory sealer SPGE 20, Hot & Cold tack heat-sealed seam strengthtester from Kopp). The heat sealing bars were replaced with two metalrails, into each of which had been milled a concavity having a diameterof 10 mm and a radius of 8 mm. The surface of the concavity is coatedwith Teflon. Once the bars have been fitted in the heat sealer, twocomplementary concavities produce a lens shape into which the tabletsare in each case placed. The heat sealing bars were heated in advance to130° C., the tablets introduced and then a force of 750 N was exertedfor 2.5 min.

The breaking strength of the tablets is determined using theabove-described method. No breakage occurred when a force of 500 N wasapplied. The tablets could not be comminuted using a hammer, nor withthe assistance of a pestle and mortar.

In vitro release of the active ingredient tramadol from the tablets wasdetermined in a paddle stirrer apparatus with sinker in accordance withPharm. Eur. The temperature of the release medium was 37° C. and therotational speed of the stirrer 75 min⁻¹. The release medium used was anintestinal juice of pH 6.8. The quantity of active ingredient releasedin each case into the dissolution medium at any one time was determinedby spectrophotometry.

Time Quantity of active ingredient released  30 min 21% 240 min 70% 480min 94% 720 min 100%

Example 2

Components Per tablet Complete batch Tramadol HCl 100.0 mg 60.0 gPolyethylene oxide, NF, MFI 221.0 mg 132.6 g (190° C. at 21.6 kg/10min)MW 5,000,000 (Polyox WSR Coagulant, Dow Chemicals)Hydroxypropylmethylcellulose  20.0 mg 12.0 g 100,000 cP (Metholose 90 SH100,000) Magnesium stearate  9.0 mg 5.4 op Total weight 350.0 mg 210.0 g

As stated in Example 1, tablets with a diameter of 10 mm and a radius ofcurvature of 8 mm were produced.

The tablets were also further processed as in Example 1, except that thesealing bars were heated to 100° C.

The breaking strength of the tablets is determined using theabove-described method. No breakage occurred when a force of 500 N wasapplied. The tablets could not be comminuted using a hammer, nor withthe assistance of a pestle and mortar.

In vitro release of the active ingredient from the preparation wasdetermined in a paddle stirrer apparatus with sinker in accordance withPharm. Eur. The temperature of the release medium was 37° C. and therotational speed of the stirrer 75 min⁻¹. The release medium used was anintestinal juice of pH 6,8. The quantity of active ingredient releasedin each case into the dissolution medium at any one time was determinedby spectrophotometry.

Time Quantity of active ingredient released  30 min 17% 240 min 60% 480min 84% 720 min 95%

Example 3

Components Per tablet Complete batch Tramadol HCl 100.0 mg  60.0 gPolyethylene oxide, NF, MFI 221.0 mg 132.6 g (190° C. at 21.6 kg/10min)MW 7,000,000, fine powder (Polyox WSR 303 FP, Dow Chemicals)Hydroxypropylmethylcellulose  20.0 mg  12.0 g 100,000 cP (Metholose 90SH 100,000) Magnesium stearate  9.0 mg  5.4 g Total weight 350.0 mg210.0 g

Tablets were produced as described in Example 1. The tablets were alsofurther processed as explained in Example 1.

The breaking strength of the tablets was determined using theabove-described method. No breakage occurred when a force of 500 N wasapplied. The tablets could not be comminuted using a hammer, nor withthe assistance of a pestle and mortar.

In vitro release of the active ingredient from the preparation wasdetermined in a paddle stirrer apparatus with sinker in accordance withPharm. Eur. The temperature of the release medium was 37° C. and therotational speed of the stirrer 75 min⁻¹. The release medium used was anintestinal juice of pH 6,8. The quantity of active ingredient releasedin each case into the dissolution medium at any one time was determinedby spectrophotometry.

Time Quantity of active ingredient released  30 min 21% 240 min 69% 480min 93% 720 min 100%

Example 4

Components Per tablet Complete batch Tramadol HCl 100.0 mg  60.0 gPolyethylene oxide, NF, MFI 221.0 mg 132.6 g (190° C. at 21.6 kg/10min)MW 7,000,000 (Polyox WSR 303, Dow Chemicals)Hydroxypropylmethylcellulose  20.0 mg  12.0 g 100,000 cP (Metholose 90SH 100,000) Magnesium stearate  9.0 mg  5.4 g Total weight 350.0 mg210.0 g

Tablets were produced as stated in Example 1.

The tablets were then heated in a microwave oven for 10 min at 700watts. Further processing proceeded as stated in Example 1, except that2 bars each comprising 5 concavities were used and, using sealing barsheated to 100° C., in each case 5 heated tablets were exposed to a forceof 1000 N for 30 seconds.

The breaking strength of the tablets is determined using theabove-described method. No breakage occurred when a force of 500 N wasapplied. The tablets could not be comminuted using a hammer, nor withthe assistance of a pestle and mortar.

Example 5

Components Per tablet Complete batch Tramadol HCl 100.0 mg  60.0 gPolyethylene oxide, NF, MFI 221.0 mg 132.6 g (190° C. at 21.6 kg/10min)MW 7,000,000 (Polyox WSR 303, Dow Chemicals)Hydroxypropylmethylcellulose  20.0 mg  12.0 g 100,000 cP (Metholose 90SH 100,000) Magnesium stearate  9.0 mg  5.4 g Total weight 350.0 mg210.0 g

Tablets were produced as stated in Example 1.

The tablets were then heated under an N₂ atmosphere in a circulating aircabinet for 45 min at 110° C.: The tablets were further processed asstated in Example 4, except that the sealing bars were heated to 130° C.

The breaking strength of the tablets is determined using theabove-described method. No breakage occurred when a force of 500 N wasapplied. The tablets could not be comminuted using a hammer, nor withthe assistance of a pestle and mortar.

Example 6

Components Per tablet Complete batch Tramadol HCl 100.0 mg  60.0 gPolyethylene oxide, NF, MFI 221.0 mg 132.6 g (190° C. at 21.6 kg/10min)MW 7,000,000 (Polyox WSR 303, Dow Chemicals)Hydroxypropylmethylcellulose  20.0 mg  12.0 g 100,000 cP (Metholose 90SH 100,000) Magnesium stearate  9.0 mg  5.4 g Total weight 350.0 mg210.0 g

Tablets were produced as stated in Example 1.

Further processing proceeded as stated in Example 1, except that thesealing bars were heated to 130° C. and the tablets were preheated inthe lower bar for 2 minutes while being exposed to a force of 10 N. Thetablets were then post-compacted with a force of 1000 N at 130° C. for20 seconds.

The breaking strength of the tablets is determined using theabove-described method. No breakage occurred when a force of 500 N wasapplied. The tablets could not be comminuted using a hammer, nor withthe assistance of a pestle and mortar.

Example 7

Components Per tablet Complete batch Tramadol HCl 100 mg 18.2 gPolyethylene oxide, NF, MW 165 mg 30.0 g 7,000,000 (Polyox WSR 303 FP,Dow Chemicals) Polyethylene glycol 6000  7 mg  1.3 g Butylhydroxytoluene 0.3 mg  0.1 g Magnesium stearate  2.7 mg  0.5 g Total weight 274.8 mg  50.0 g

The stated quantity of butylhydroxytoluene was dissolved in 0.6 g ofethanol (96%). This solution was mixed with the polyethylene glycol 6000and then dried at 40° C. for 12 hours. All the further components apartfrom magnesium stearate were added and mixed for 15 min in a free-fallmixer. The magnesium stearate was then mixed in. The mixture wasscreened with a 0.8 mm screen.

Using a Korsch EK0 eccentric press, tablets were produced from thescreened mixture (diameter: 10 mm and radius of curvature: 8 mm). Thesewere then heated to 80° C. in a drying cabinet under an N₂ atmospherefor 15 minutes.

The hot tablets were pressed again on an eccentric press (Kilian/IMA,model SP 300) with a force of 80 kN. The tool used was a tablettingpunch with a diameter of 11 mm and a radius of curvature of 8 mm.

The breaking strength of the tablets was determined using theabove-described method. No breakage occurred when a force of 500 N wasapplied. The tablets could not be comminuted using a hammer, nor withthe assistance of a pestle and mortar.

In vitro release of the active ingredient from the preparation wasdetermined in a paddle stirrer apparatus with sinker in accordance withPharm. Eur. The temperature of the release medium was 37° C. and therotational speed of the stirrer 75 min−¹. The release medium used wasintestinal juice with a pH of 6.8. The quantity of active ingredientreleased in each case into the dissolution medium at any one time wasdetermined by spectrophotometry.

Time Quantity of active ingredient released  30 min 17% 240 min 65% 480min 87% 720 min 95%

1. A process for the production of a solid pharmaceutical dosage formswith at least reduced potential for abuse, comprising: a) shaping aformulation mixture into formed articles by application of force, theformulation mixture comprising at least one active ingredient withpotential for abuse, at least one synthetic or natural polymer (C),which exhibits a breaking strength of at least 500 N, and optionallyauxiliary substances (B); b) optionally singulating and optionally ineach case grading the formed articles by size and, c) after or duringheating at least to the softening point of the polymer (C), exposing theformed articles to force until they have a breaking hardness of at least500 N, and optionally providing them with a cover and optionally mixingall the formed articles back together again.
 2. A process according toclaim 1, which is performed continuously or discontinuously.
 3. Aprocess according to claim 1, wherein the formulation mixture consiststo an extent of at least 30 wt. % of component (C).
 4. A processaccording to claim 1, wherein the formulation mixture consists to anextent of at least 50 wt. % of component (C).
 5. A process according toclaim 1, wherein a) shaping of the formulation mixture proceeds withapplication of a force of at least 0.5 kN and optionally with heating toless than 60° C.
 6. A process according to claim 1, wherein, accordingto c), the formed articles are heated to at least 60° C. before orduring application of force of at least 0.1 kN.
 7. A process accordingto claim 1, wherein the application of force according to a) or c) isperformed with the assistance of a press, shaping rollers or withshaping belts equipped with rollers.
 8. A process according to claim 1,wherein shaping according to a) gives rise to tablets.
 9. A processaccording to claim 1, wherein shaping according to a) gives rise to amultiparticulate dosage form with a minimum size of 0.5 mm.
 10. Aprocess according to claim 1, wherein opioid active ingredients are usedas active ingredients.